Activation of goblet cell stress sensor IRE1β is controlled by the mucin chaperone AGR2

Abstract

As secretory cells specialized in the production of mucins, intestinal goblet cells are challenged by the need for efficient protein folding. Goblet cells express Inositol-Requiring Enzyme 1{beta} (IRE1{beta}), a unique unfolded protein response (UPR) sensor that is part of an adaptive mechanism that regulates the demands of mucin production and secretion. However, how IRE1{beta} activity is tuned to mucus folding load remains unknown. We identified the disulfide isomerase and mucin chaperone AGR2 as a goblet cell specific protein that crucially regulates IRE1{beta}-, but not IRE1-mediated signaling. AGR2 binding to IRE1{beta} disrupts IRE1{beta} dimerization, thereby blocking its downstream endonuclease activity. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1{beta} activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum sets the threshold for IRE1{beta} activation. We found that AGR2 mutants lacking their catalytic cysteine or displaying the disease-associated mutation H117Y were no longer able to dampen IRE1{beta} activity. Collectively, these results demonstrate that AGR2 is a central chaperone regulating the goblet cell UPR by acting as a rheostat of IRE1{beta} endonuclease activity.